Anxious mice calmed with brain flashes

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Behind the Headlines

Thursday March 10 2011

Many would object to optical fibres inserted into their brain

People who suffer from anxiety could have their fear banished as scientists have “identified a brain mechanism that makes individuals fearless”, the Daily Mail reported. It said that tests on mice showed that “triggering the mechanism with pulses of light boosted their willingness to take risks, while inhibiting it rendered them more timid”.

As the Daily Mail reports, this study was in mice and explored how certain areas of the brain are involved in anxiety. The research used a technique in which genetically engineered viruses containing photosensitive proteins (proteins sensitive to light) were inserted into the brains of mice. The proteins were then exposed to flashes of light through surgically implanted optical fibres. Stimulating a particular part of the amygdala (a region of the brain thought to have a role in emotion and anxiety) reduced anxious behaviour in the mice, while inhibiting it increased the behaviour. Notably, the effects were instantaneous and reversible, and did not occur when control mice were stimulated with the light.

This experimental animal study was carefully conducted and used an appropriate design and methods. The study has limited relevance for the treatment of anxiety in humans at this point as it seems unlikely that the methods used here would be an acceptable treatment for humans.

Where did the story come from?

The study was carried out by researchers from the Departments of Bioengineering, Psychiatry and Neuroscience at Stanford University in California. It was supported by multiple grants and awards, including some from the National Institutes of Health and a Samsung Scholarship. The study was published as a Letter in the peer-reviewed science journal Nature.

The Daily Mail covered the main details of the research accurately, but has exaggerated the relevance of the experimental procedure as a new treatment. Although a greater understanding of the nerve systems involved in anxiety may lead to improved treatments, the complex experimental procedure used in this study (involving genetic manipulation of the nerve cells and implantation of optical fibres into the brain) is unlikely to be feasible in humans.

What kind of research was this?

This was an animal study in mice. The researchers say that, despite anxiety disorders being common, the underlying nerve circuitry in the brain is not well understood. The region of the brain called the amygdala is thought to have a role in emotion and anxiety. In this study, they wanted to pin down more precisely the subregions and connections within this area that could be responsible for anxiety.

As most of the available treatments for anxiety are either not very effective, have side effects or are addictive, a better understanding of the underlying nerve circuitry in the brain could improve treatment. The researchers used a relatively new technique for studying brain activity called optogenetics to study the effects of anxiety in mice.

What did the research involve?

In this animal study, the researchers used optogenetics to explore the neural circuits underlying anxiety-related behaviours. They measured anxiety in the mice using standard techniques and also examined their brain “electrophysiology” (its electrical activity).

The researchers looked at the amygdala. Within this area there are subregions called the basolateral amygdala and the central nucleus of the amygdala. The researchers were particularly interested in whether the nerves in the basolateral amygdala that connect with the central nucleus of the amygdala are involved in anxiety, so these were the nerves they targeted in their experiments.

Optogenetics is a relatively new technique used to study brain activity. The process involves the injection of a virus that is genetically engineered to carry photosensitive proteins into the brain. The virus introduces the photosensitive proteins into the neurons in the brain, making them susceptible to manipulation by exposure to light.

The researchers injected such a virus directly into the brains of three groups of mice. This virus had been engineered to carry genes that contain the code for a photosensitive protein similar to a protein found in the light-sensitive cells at the back of the eye. In this study, two different photosensitive proteins were used, one that would activate the nerve cells when exposed to light, and one that would inhibit these nerve cells when exposed to light. One of the groups was given the activating proteins, one the inhibiting proteins, and the third was not injected with any proteins, but just given the light stimulation.

To illuminate particular nerve fibres (the neuronal fibres) in the central nucleus of the amygdala, the researchers inserted an optical fibre through a small cannula in the brain. They then collected data on how the animals behaved and any electrophysiological or imaging data four to six weeks after surgery.

The light stimulation was delivered via optical fibres while the mice were free to move around their box. The researchers recorded the mouse movements. Mice usually try to avoid open spaces because such places leave them exposed to predators. If they’re anxious they normally move around the edges of their boxes without straying into the middle. However, as they become calmer they leave the safety of the edges.

What were the basic results?

The researchers say that light stimulation to the terminals in the central nucleus of the amygdala produced a quick but reversible reduction in anxiety. When mice that had been given the photosensitive proteins to inhibit nerve cells were stimulated, they demonstrated increased anxiety-related behaviours.

How did the researchers interpret the results?

The researchers conclude that their results indicate that this specific circuit of the amygdala is a critical brain circuit for acute anxiety control in the brain of mammals. They say the research demonstrates the importance of optogenetically targeting specific cell connections rather than single cell types. They suggest these results are relevant to the investigation of neuropsychiatric disease.

Conclusion

This research demonstrates the use of a relatively new technique called optogenetics. This technique is likely to be used in many more animal experiments aimed at understanding the role of different circuits within the brain.

This experimental animal study was carefully conducted and used an appropriate design and methods.

The fact that light stimulation produced effects that were instantaneous and reversible, and that the effects did not occur in the control mice suggests that the researchers have correctly identified the areas involved in producing anxiety in mice. The findings suggest that anxiety is continuously controlled by the balance between negative and positive pathways within the amygdala, and further research of this type is likely to clarify the pathways and their interactions better.

A few limitations are mentioned by the researchers, including the fact that the findings do not exclude other nearby circuits in the amygdala that could also be involved in anxiety control.

The study has limited relevance for the treatment of anxiety in humans at this point. It seems unlikely that injecting modified viruses containing photosensitive proteins into human brains and then surgically implanting optical fibres would be an acceptable treatment for anxiety.